C/EBPα-mediated ACSL4-dependent ferroptosis exacerbates tubular injury in diabetic kidney disease.

IF 6.1 2区生物学 Q1 CELL BIOLOGY

Cell Death Discovery Pub Date : 2024-10-23 DOI:10.1038/s41420-024-02179-w

Ziru Xia, Zhaonan Wei, Xin Li, Yunzi Liu, Xiangchen Gu, Jianhua Tong, Siyi Huang, Xiaoyue Zhang, Weiming Wang

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Abstract

Diabetic kidney disease (DKD) is a prevalent and debilitating complication of diabetes characterized by progressive renal function decline and a lack of effective treatment options. Here, we investigated the role of the transcription factor CCAAT/enhancer binding protein alpha (C/EBPα) in DKD pathogenesis. Analysis of renal biopsy samples revealed increased C/EBPα expression in patients with DKD. Using RNA sequencing and proteomics, we explored the mechanisms through which the C/EBPα contributes to DKD. Our findings demonstrated that C/EBPα exacerbated tubular injury by promoting acyl-CoA synthetase long-chain family member 4 (ACSL4)-dependent ferroptosis. We identified that C/EBPα upregulated ACSL4 expression by binding to its transcription regulatory sequence (TRS), leading to elevated lipid peroxidation and ferroptosis. Furthermore, inhibition or genetic ablation of C/EBPα attenuated ferroptosis and mitigated tubular injury in DKD. These results highlighted the C/EBPα-ACSL4-ferroptosis pathway as a promising therapeutic target for DKD treatment.

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C/EBPα介导的 ACSL4 依赖性铁蛋白沉积会加剧糖尿病肾病的肾小管损伤。

糖尿病肾病（DKD）是一种常见的、使人衰弱的糖尿病并发症，其特点是肾功能进行性衰退和缺乏有效的治疗方案。在此，我们研究了转录因子 CCAAT/增强子结合蛋白α（C/EBPα）在 DKD 发病机制中的作用。肾活检样本分析显示，DKD 患者体内 C/EBPα 表达增加。利用 RNA 测序和蛋白质组学，我们探索了 C/EBPα 促成 DKD 的机制。我们的研究结果表明，C/EBPα通过促进酰基-CoA合成酶长链家族成员4（ACSL4）依赖性铁变态反应，加剧了肾小管损伤。我们发现，C/EBPα通过与其转录调控序列（TRS）结合，上调了ACSL4的表达，从而导致脂质过氧化和铁变态反应的加剧。此外，抑制或基因消减 C/EBPα 可减轻 DKD 中的铁蛋白沉积和肾小管损伤。这些结果突出表明，C/EBPα-ACSL4-铁蛋白沉积途径是治疗DKD的一个很有前景的治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell Death Discovery Biochemistry, Genetics and Molecular Biology-Cell Biology

CiteScore

8.30

自引率

1.40%

发文量

468

审稿时长

9 weeks

期刊介绍： Cell Death Discovery is a multidisciplinary, international, online-only, open access journal, dedicated to publishing research at the intersection of medicine with biochemistry, pharmacology, immunology, cell biology and cell death, provided it is scientifically sound. The unrestricted access to research findings in Cell Death Discovery will foster a dynamic and highly productive dialogue between basic scientists and clinicians, as well as researchers in industry with a focus on cancer, neurobiology and inflammation research. As an official journal of the Cell Death Differentiation Association (ADMC), Cell Death Discovery will build upon the success of Cell Death & Differentiation and Cell Death & Disease in publishing important peer-reviewed original research, timely reviews and editorial commentary. Cell Death Discovery is committed to increasing the reproducibility of research. To this end, in conjunction with its sister journals Cell Death & Differentiation and Cell Death & Disease, Cell Death Discovery provides a unique forum for scientists as well as clinicians and members of the pharmaceutical and biotechnical industry. It is committed to the rapid publication of high quality original papers that relate to these subjects, together with topical, usually solicited, reviews, editorial correspondence and occasional commentaries on controversial and scientifically informative issues.